Defects in primary cilium formation and function are responsible for a variety of human diseases and developmental disorders, collectively termed ciliopathies. While the ciliopathies are diverse in both phenotype and etiology, specific genes, including CEP290, have been implicated as having causative roles in multiple cilium-associated disorders. Mutations in the gene CEP290 have been described in up to 20% of cases of the devastating inherited blinding disease Leber congenital amaurosis and in numerous cases of other more debilitating ciliopathies, such as Joubert syndrome, Senior Loken Syndrome, and Meckel-Gruber syndrome. These disorders range in severity from isolated retinal degeneration to renal dysfunction, central nervous system malformations, hepatic development defects, and embryonic lethality.
Attempts to treat genetic defects have been attempted by delivery of normal genes to the cells expressing the defective genes, such as recombinant adeno-associated virus (AAV)-based therapeutics. See, e.g., U.S. Pat. No. 8,147,823. Generally, large gene sequences have been difficult to fit effectively into some of the more useful vector delivery systems. The extension, to CEP290 patients, of recombinant adeno-associated virus (AAV)-based therapeutics, which have proven safe and effective in the treatment of another genetic cause of LCA, has been hindered by CEP290's large size, precluding it from packaging in AAV.
There remains a need in the art for additional therapeutic compositions and methods for treatment of LCA and other ciliopathies.